Immunotherapies in Combination With Stereotactic Body Radiation Radiotherapy in Microsatellite Stable (MSS) Metastatic Colorectal Cancer (mCRC)

Background: * Metastatic colorectal cancer (mCRC) is incurable for most patients and carries a poor diagnosis. * Immune-based approaches in solid tumor malignancies have seen much progress but these have limited efficacy for microsatellite stable (MSS) mCRC. * The Gastrointestinal Malignancies Section at NCI conducted a Pilot Study of the PD-1 Targeting Agent AMP-224 with low-dose cyclophosphamide and stereotactic body radiation therapy (SBRT) that supports potential antitumor efficacy of the combination of immunotherapy and radiation in MSS mCRC (NCT02298946). * T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed in multiple cancers on tumor-infiltrating cytotoxic T cells, helper T cells, natural killer (NK) cells, and regulatory T cells. Its main ligand, CD155, is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, contributing to local immune-surveillance suppression. * Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. * Pre-clinical studies show that the co-blockade of TIGIT and the programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) pathway may lead to decreased tumor volume. Notably, this has been observed in anti-PD-1 resistant tumor models. * Preclinical and clinical evidence suggests further increased benefit to the double immune checkpoint blockade through increased expression of PD-L1 and neoantigens in response to SBRT. * Early results from clinical trials suggest clinical activity of anti-TIGITplus anti-PD-L1 in solid tumors and the effect of combining immunotherapy with radiation in heavily pretreated MSS mCRC patients providing a proof of concept that radiation enhances immunotherapy response. * A combination of anti-PD-L1, anti-TIGIT, and SBRT may increase CRC susceptibility to immune therapy given the promising activity of anti-TIGIT in combination with anti-PDL1 in preclinical studies of mice bearing subcutaneous CT26 colon tumors. Primary Objectives: * To confirm the Recommended Phase II dose (RP2D) of the combination therapy (tiragolumab and atezolizumab plus SBRT) in participants with MSS mCRC (Part A) * To determine the proportion of participants without progression after 9 weeks of the combination therapy (tiragolumab and atezolizumab plus SBRT) in participants with MSS mCRC (Part B) Eligibility: * Age \>= 18 years * Eastern Cooperative Oncology Group (ECOG) performance status \<= 1 * Histopathologic confirmation of mCRC by the NCI Laboratory of Pathology (LP) * Disease not amenable to curative resection * At least 1 lesion amenable to SBRT and a second lesion outside the radiation field to serve as a target lesion * Adequate organ and marrow function Design: * This is a phase II, single-arm, non-randomized, trial using tiragolumab and atezolizumab in combination with SBRT. * A maximum of 30 participants with MSS mCRC will be enrolled. * Participants will receive atezolizumab and tiragolumab intravenously (IV) every 3 weeks (21-day cycles) with SBRT occurring on Days 1, 3, and 5 of Cycle 1 for 2 years. * Participants will be evaluated routinely for toxicity and will have re-staging imaging every 9 weeks (every 3 cycles). * Optional research biopsies will be done at baseline and during week 1 of cycle 2. If the participant has disease progression after cycle 3, a post-treatment biopsy may be performed. * The proportion of participants that are progression-free at 9 weeks will be evaluated as a binary endpoint.